I am a pediatric intensivist and anesthesiologist with a PhD in physiology. My principal clinical interests are neuronal injury and chronic pain. This research proposal develops the principles and methods of controlled release technology to produce prolonged duration local anesthetics. This mentored research in chemical engineering, molecular biology and neurobiology, in conjunction with appropriate coursework, will foment competence in biotechnological approaches to medical problems. These approaches are potentially germane to a wide range of medical applications and substrates (peptides, genes, even cells). Thus, this program will foster the abilities and mindset necessary to train me to be an independent investigator. Chronic pain is a major cause of morbidity, particularly in patients suffering from cancer or neuropathic conditions. These painful states are often refractory to therapy. This research will endeavor to produce polymer-based particles containing compounds with local anesthetic properties in order to achieve pain relief lasting many weeks. In particular, the novel formulations will take advantage of synergistic interactions between conventional amino amide local anesthetics and site 1 sodium channel blockers, as well as the potentiating effect of adjuncts such as glucocorticoids. Selection of the optimal site 1 sodium channel blocker for this project will result from a pharmacological comparison in terms of efficacy, functional selectivity, and toxicity. The selected toxin 'will then be encapsulated in poly-(lactic- co-glycolic) acid microspheres, which will then be optimized in term of loading and in vitro release kinetics. These microspheres will be tested with respect to efficacy (depth, duration, and functional selectivity of nerve blockade) and systemic toxicity (systemiC analgesia, weakness, respiratory distress, seizures, death) when injected alone, or in conjunction with microspheres containing bupivacaine and/or dexamethasone. The biological consequences and local neurotoxicity of these formulations will be investigated by a) histologic assessment of inflammation, b) examination for the development of pain-related behaviors such as autotomy, which are believed to be related to neuropathic pain, c) measuring their impact on the expression of Growth Associated Peptide-43 (GAP-43), a cytoskeletal phosphoprotein that has been associated with the neural response to injury, in the dorsal root ganglia of the sciatic nerve. Finally, we will study the effectiveness of prolonged duration local anesthesia in preventing or mitigating the development of pain-related behaviors and the rise in GAP-43 expression following nerve crush injury.